1. Fenofibrate insulates diacylglycerol in lipid droplet/ER and preserves insulin signaling transduction in the liver of high fat fed mice.
- Author
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Chan SM, Zeng XY, Sun RQ, Jo E, Zhou X, Wang H, Li S, Xu A, Watt MJ, and Ye JM
- Subjects
- Animals, Diet, High-Fat adverse effects, Endoplasmic Reticulum drug effects, Fatty Liver etiology, Lipid Droplets drug effects, Liver drug effects, Liver metabolism, Liver pathology, Male, Mice, Mice, Inbred C57BL, PPAR alpha metabolism, Signal Transduction, Diglycerides metabolism, Endoplasmic Reticulum metabolism, Fatty Liver metabolism, Fenofibrate pharmacology, Hypolipidemic Agents pharmacology, Insulin metabolism, Lipid Droplets metabolism
- Abstract
Hepatic steatosis is often associated with insulin resistance as a hallmark of the metabolic syndrome in the liver. The present study investigated the effects of PPARα activation induced by fenofibrate (FB) on the relationship of insulin resistance and hepatic steatosis in mice fed a high-fat (HF) diet, which increases lipid influx into the liver. Mice were fed HF diet to induce insulin resistance and hepatic steatosis with or without FB. FB activated PPARα and ameliorated HF diet-induced glucose intolerance and hepatic insulin resistance without altering either hepatic steatosis or inflammation signaling (JNK or IKK). Interestingly, FB treatment simultaneously increased fatty acid (FA) synthesis (50%) and oxidation (66%, both p<0.01) into intermediate lipid metabolites, suggesting a FA oxidation-synthesis cycling in operation. Associated with these effects, diacylglycerols (DAGs) were sequestered within the lipid droplet/ER compartment, thus reducing their deposition in the cellular membrane, which is known to impair insulin signal transduction. These findings suggest that the reduction in membrane DAGs (rather than total hepatic steatosis) may be critical for the protection by fenofibrate-induced PPARα activation against hepatic insulin resistance induced by dietary fat., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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